rs139548132

chr1-119140608-A-Cchr1-119140608-A-Gchr1-119140608-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM5 BP4_Strong BS2

The NM_015836.4(WARS2):c.37T>G(p.Trp13Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,613,944 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W13R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0036 (22 hom.)
• Consequence: WARS2 NM_015836.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:10 U:5 B:2
• Conservation: PhyloP100: -0.145

Genes affected

WARS2 (HGNC:12730): (tryptophanyl tRNA synthetase 2, mitochondrial) Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Two forms of tryptophanyl-tRNA synthetase exist, a cytoplasmic form, named WARS, and a mitochondrial form, named WARS2. This gene encodes the mitochondrial tryptophanyl-tRNA synthetase. Two alternative transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

WARS2-AS1 (HGNC:40612): (WARS2 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-119140608-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3233281.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0043417513).
• BS2: High Homozygotes in GnomAdExome at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WARS2	NM_015836.4	c.37T>G	p.Trp13Gly	missense_variant	1/6	ENST00000235521.5
WARS2-AS1	NR_125975.1	n.213A>C		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WARS2	ENST00000235521.5	c.37T>G	p.Trp13Gly	missense_variant	1/6	1	NM_015836.4	P1

Frequencies

GnomAD3 genomes AF: 0.00315 AC: 480 AN: 152276 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000844

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00489

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00322 AC: 809 AN: 250992 Hom.: 6 AF XY: 0.00352 AC XY: 478 AN XY: 135722

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.00357

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00379

Gnomad FIN exome AF: 0.000695

Gnomad NFE exome AF: 0.00436

Gnomad OTH exome AF: 0.00636

GnomAD4 exome AF: 0.00363 AC: 5311 AN: 1461550 Hom.: 22 Cov.: 30 AF XY: 0.00372 AC XY: 2703 AN XY: 727072

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00418

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00369

Gnomad4 FIN exome AF: 0.000880

Gnomad4 NFE exome AF: 0.00398

Gnomad4 OTH exome AF: 0.00404

GnomAD4 genome AF: 0.00315 AC: 480 AN: 152394 Hom.: 0 Cov.: 33 AF XY: 0.00305 AC XY: 227 AN XY: 74520

Gnomad4 AFR AF: 0.000841

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.000470

Gnomad4 NFE AF: 0.00489

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00423 Hom.: 2

Bravo AF: 0.00300

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.00331 AC: 402

EpiCase AF: 0.00616

EpiControl AF: 0.00510

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:10 Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures Pathogenic:4 Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Nov 16, 2020	The heterozygous p.Trp13Gly variant in WARS2 was identified by our study in the compound heterozygous state, along with another variant of unknown significance, in 1 individual with neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures. The variant has been reported in at least 7 individuals, of varied ethnicities, with neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures (PMID: 29120065, 28236339, 32120303, 30831263, 31970218). This variant has been identified in 0.46% (590/128958) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs139548132) and was detected in homozygosity in 6 control individuals from various populations, suggesting that this variant is not pathogenic for neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures. This variant has also been reported in ClinVar (Variation ID: 440915) as likely benign by Invitae, pathogenic by OMIM and Institute of Human Genetics, Klinikum rechts der Isar, likely pathogenic by Reproductive Health Research and Development, BGI Genomics, and as having unknown significance by CeGaT Praxis fuer Humangenetik Tuebingen. Of the 7 affected individuals, 2 were compound heterozygotes that carried a reported likely pathogenic variants in trans and 2 were compound heterozygotes that carried variants of uncertain significance in trans which increases the likelihood that the p.Trp13Gly variant is pathogenic (Variation ID: 440914, 807717; PMID: 29120065, 28236339, 32120303, 30831263, 31970218). In vitro functional studies provide some evidence that the variant may impact protein function (PMID: 29120065, PMID: 28236339). However, these types of assays may not accurately represent biological function. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein. In summary, while the clinical significance of the p.Trp13Gly variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1, BS2, PS3_moderate, PM3, BP4 (Richards 2015). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Feb 28, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 05, 2022	- -
Likely pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_015836.3:c.37T>G in the WARS2 gene has an allele frequency of 0.006 in other subpopulation in the gnomAD database. Functional studies demonstrate that c.37T>G has affected a mitochondrial signal peptide (SP) leading to mislocalization of the mutant protein in the cells (PMID: 28236339). It was detected in individual with autosomal recessive Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures, compound heterozygous with c.325delA (PMID: 28236339). Benign computational verdict because benign predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationTaster, PrimateAI, REVEL and SIFT. Taken together, we interprete this variant as Pathogenic/Likely pathogenic variant. ACMG/AMP criteria applied: PS3; PM3; BP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Parkinsonism-dystonia 3, childhood-onset Pathogenic:2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	May 05, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Apr 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 01, 2022	- -

not provided Pathogenic:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28236339, 30920170, 33611074, 34890876, 32120303, 31970218, 33619735, 29120065, 30831263, 34958143, 35795805, 35872528, 33949708, 35074316) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 01, 2022	- -

WARS2-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 03, 2023	Variant summary: WARS2 c.37T>G (p.Trp13Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 250992 control chromosomes in the gnomAD database, including 6 homozygotes. c.37T>G has been reported in the literature in numerous compound heterozygous individuals affected with WARS2-Related Disorders, including several patients with infantile-onset Parkinsonism (e.g., Musante_2017, Burke_2018, Nogueira_2019, Hubers_2019, Martinelli_2002, Brunet_2021, Skorvanek_2022); pathogenic variants have been confirmed in trans in the majority of these individuals and the variant has been shown to segregate with disease in related individuals. These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function, finding that the variant results in impaired mitochondrial localizaiton in vitro (e.g., Musante_2017), and in compound heterozygous patient fibroblasts, results in reduced WARS2 protein levels and impairs mitochondrial respiratory chain activity (e.g., Burke_2018, Martinelli_2020, Skorvanek_2022). The following publications have been ascertained in the context of this evaluation (PMID: 33619735, 29120065, 31970218, 32120303, 28236339, 30831263, 34890876). Multiple ClinVar submitters (evaluation after 2014) have reported the variant with conflicting assessments: pathogenic (n = 4), likely pathogenic (n = 2), VUS (n = 4), and likely benign (n = 2). The presence of homozygotes in the gnomAD control population as well as the many patients found to harbor this variant and functional evidence combine to suggest this variant represents a hypomorphic allele. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 24, 2023	The WARS2 c.37T>G variant is predicted to result in the amino acid substitution p.Trp13Gly. The c.37T>G (p.Trp13Gly) variant has been described as a hypomorphic allele and reported in the compound heterozygous state in multiple unrelated families affected with intellectual disability or infantile onset leukoencephalopathy (Musante et al. 2017. PubMed ID: 28236339 ; Burke et al. 2018. PubMed ID: 29120065; Nogueira et al. 2019. PubMed ID: 30831263; Martinelli et al. 2020. PubMed ID: 32120303; Hubers et al. 2020. PubMed ID: 31970218; Skorvanek et al. 2022. PubMed ID: 34890876). In vitro study showed this variant may affect the mitochondrial localization signal (Musante et al. 2017. PubMed ID: 28236339). This variant is reported in 0.46% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including 6 homozygous individuals of unknown phenotype (http://gnomad.broadinstitute.org/variant/1-119683231-A-C), and is only expected to cause disease when found in trans (on the opposite chromosome) with a second more deleterious variant in this gene (Skorvanek et al. 2022. PubMed ID: 34890876). Based on the collective evidence, we interpret this variant to be a likely pathogenic variant. -

Neurodevelopmental disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 29, 2024

The p.Trp13Gly variant in WARS2 has been reported in the compound heterozygous state in >15 individuals with WARS2-associated disorders including infantile-onset parkinson's disease, dystonia and neurodevelopmental disorder. In at least 5 individuals, the p.Trp13Gly variant was identified along with another disease causing variant in WARS2 (Musante 2017 PMID: 28236339, Burke 2018 PMID: 29120065, Hubers 2019 PMID: 31970218, Nogueira 2019 PMID: 30831263, Martinelli 2020 PMID: 32120303, Brunet 2021 PMID: 33619735, Dzinovic 2022 PMID: 35872528, Gabriel 2022 PMID: 34958143, Skorvanek 2022 PMID: 34890876, Pauly 2023 PMID: 37107582). This variant segregated in 3 affected relatives from 2 families (Musante 2017 PMID: 28236339, Skorvanek 2022 PMID: 34890876). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 440915) and has been identified in 0.77% (47/6060) of Middle Eastern and 0.4% (251/60006) of Admixed Americans chromosomes including 22 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v4.0.0). In vitro studies provide some evidence that this variant impacts protein function by impairing mitochondrial localization and a reduction of protein level and consequently affecting mitochondrial respiratory chain activity (Musante 2017 PMID: 28236339, Burke 2018 PMID: 29120065) but computational prediction tools and conservation analyses suggest that this variant may not impact the protein. Since this variant has been identified in the homozygous state in multiple individuals in gnomAD, the variant most likely represents a hypomorphic allele and is only expected to cause disease when found in trans with a second more deleterious variant in this gene, such as a loss of function variant. It is not expected to cause disease in the homozygous state. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive WARS2 deficiency. ACMG/AMP Criteria applied: PM3_Strong, PP1_Strong, PS3_Supporting, BS4. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2021

The c.37T>G (p.W13G) alteration is located in exon 1 (coding exon 1) of the WARS2 gene. This alteration results from a T to G substitution at nucleotide position 37, causing the tryptophan (W) at amino acid position 13 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	16
Dann	Benign	0.89
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.0043	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	0.96	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.74	N;N
REVEL	Benign	0.12
Sift	Benign	0.081	T;T
Sift4G	Uncertain	0.016	D;T
Polyphen		0.0010	.;B
Vest4		0.43
MVP		0.25
MPC		0.74
ClinPred		0.037	T
GERP RS		0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs139548132; hg19: chr1-119683231; COSMIC: COSV99346234; COSMIC: COSV99346234;